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PONE-D-23-27887Energy Landscape Analysis and Time-series Clustering Characterizes Patient State Multi-stability Related to Rheumatoid Arthritis Drug Treatment: The KURAMA Cohort StudyPLOS ONE

Dear Dr. Yamamoto,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Specifically, both reviewers found some interests in this study, but also pointed out a number of concerns that require improvement or amendment. I request you to respond to all comments made by reviewers in the revised version. 

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Academic Editor

PLOS ONE

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2. Thank you for stating the following in the Competing Interests section: 

"The Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, is supported by Nagahama City, Shiga, Japan; Toyooka City, Hyogo, Japan; Asahi Kasei Pharma Corp.; and AYUMI Pharmaceutical Co. MH received research grants and/or speaker fees from Abbvie, Asahi Kasei, Astellas, Ayumi, Brystol Meyers, Chugai, EA Pharma, Eisai, Daiichi Sankyo, Eli Lilly, Novartis Pharma, and Tanabe Mitsubishi. M.T. received research grants and/or speaker fees from AbbVie GK, Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Pfizer Inc., Taisho Pharmaceutical Co., Ltd., Tanabe Mitsubishi Pharma Corp., Teijin Pharma, Ltd., and UCB Japan Co., Ltd. K.M. received speaking and/or consulting fees from AbbVie GK, Eisai Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Bristol-Myers Squibb, Daiichi Sankyo Co., Ltd., Janssen Pharmaceutical K.K., and Asahi Kasei Pharma Corp. The other authors declare that they have no conflicts of interest."

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The reviewer thinks this is an interesting analysis method that takes into account time variation.

Major comments:

1. The approach of combining two analysis methods is novel. The authors need to expound upon the reasoning behind merging these two methods. How do the two methods' shortcomings balance each other out when combined?

2. Using "energy" as a descriptor for the change in disease activity is intriguing. While the results seem to be clinically consistent with evaluating changes in disease activity, what fresh insights does this study offer by adopting such a perspective?

3. In the "Interpretation" section, the authors highlight the quantitative elucidation of significant treatment effects in terms of timing and duration. Please specify which particular result or findings you are referencing here.

4. Furthermore, in the "Interpretation" section, there is a suggestion that for certain patients who might be heading towards a treatment dead-end, a more potent treatment choice could be essential. Given that this study is anchored in a T2T-based approach, is it conceivable that such enhanced treatment decisions could be made?

Minor comments:

1. The units of measurement must be explicitly stated in the table for clarity.

2. On Page 5, Line 50, the statement "The importance of early disease detection and treatment initiation." stands incomplete. Kindly provide context or rephrase for completeness.

Reviewer #2: Dear authors,

The uniqueness of this manuscript was that the authors used energy landscape analysis and time-series clustering, which are methods different from common multivariate regression analysis, to examine the stability- and instability-based behavior of RA patients. This methodology and findings are interesting and the manuscript has a potential of interest, however, there are some concerns on this manuscript.

1． The major problem of this manuscript is the definition of the terms "Stability" and "Remission". The authors should better to make sure the definitions and keep those terms consistently throughout the manuscript.

(1) The term "remission" appears in this manuscript at several different situations and each implies a different meaning. For example, the word "remission" is used in "good stability leading to remission" and it used in each of the variables used in the energy landscape analysis. Additionally, the definition of "good stability" is "functional remission". From the above, it is necessary that the readers should guess the meaning of "remission" each time when it appears. I suggest that the authors consider improving on this terminology of “remission”.

(2) In the methods section, the authors described that, “Good stability” was defined as meeting functional remission criteria based on the Health Assessment Questionnaire (HAQ), and “poor stability” was defined as dying or falling below the energy threshold without functional remission. This complicated definition makes it very difficult to understand Figure 5. According to the definition, G-L seems to be a combination of good stability = functionally good state and Low-energy = stability (+), which is still understandable. However, the most difficult one is the P-H combination, which is a combination of poor stability = functionally poor with falling below the threshold of energy (stability +) and High-energy = stability (-). This was quite confusing for the readers. I think that the "stability" is essentially defined from the result of high or low energy by energy landscape analysis.

(3) The authors probably described Poor as Bad initially. I have found remnants of this in the text and in the Figure caption, Table. This made it very difficult to read, especially in the case of abbreviations such as B-L, as I could not keep up with their understanding. Please make sure to use the word "Poor" in a consistent manner.

(4) Please clarify 1) and 2) above and then rewrite Figure 1. This is the figure that confused me the most because the terms of “Good or Poor stability”, “remission” are mixed up in this figure. As a minor point, the word "Energy-igh" in the figure is probably a typo for -high, so please correct it.

2．In Figure 5, a 4x4 analysis is performed using the high and low scores derived from the energy landscape analysis and the good or poor stability defined by the HAQ. Is there any correlation or relationship between the total value of each activity variables used in the energy landscape analysis and HAQ?

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Reviewer #1: No

Reviewer #2: Yes: Yasushi Kondo

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Energy landscape analysis and time-series clustering analysis of patient state multistability related to rheumatoid arthritis drug treatment: the KURAMA cohort study

PONE-D-23-27887R1

Dear Dr. Yamamoto,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Masataka Kuwana, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors well revised and answered our review comments. This version appeared better for publications. Findings are also important for future discussion.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Yasushi Kondo

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